Adipose-derived adult stem cells for cartilage tissue engineering.
Tissue engineering is a promising therapeutic approach that uses combinations of implanted cells, biomaterial scaffolds, and biologically active molecules to repair or regenerate damaged or diseased tissues. Many diverse and increasingly complex approaches are being developed to repair articular cartilage, with the underlying premise that cells introduced exogenously play a necessary role in the success of engineered tissue replacements. A major consideration that remains in this field is the identification and characterization of appropriate sources of cells for tissue-engineered repair of cartilage. In particular, there has been significant emphasis on the use of undifferentiated progenitor cells, or "stem" cells that can be expanded in culture and differentiated into a variety of different cell types. Recent studies have identified the presence of an abundant source of stem cells in subcutaneous adipose tissue. These cells, termed adipose-derived adult stem (ADAS) cells, show characteristics of multipotent adult stem cells, similar to those of bone marrow derived mesenchymal stem cells (MSCs), and under appropriate culture conditions, synthesize cartilage-specific matrix proteins that are assembled in a cartilaginous extracellular matrix. The growth and chondrogenic differentiation of ADAS cells is strongly influenced by factors in the biochemical as well as biophysical environment of the cells. Furthermore, there is strong evidence that the interaction between the cells, the extracellular biomaterial substrate, and growth factors regulate ADAS cell differentiation and tissue growth. Overall, ADAS cells show significant promise for the development of functional tissue replacements for various tissues of the musculoskeletal system.


Sedentary Behavior and Cardiovascular Disease Risk: Mediating Mechanisms.
Sedentary behavior has a strong association with cardiovascular disease (CVD) risk, which may be independent of physical activity. To date, the mechanism(s) that mediate this relationship are poorly understood. We hypothesize that sedentary behavior modifies key hemodynamic, inflammatory, and metabolic processes resulting in impaired arterial health. Subsequently, these vascular impairments directly and indirectly contribute to the development of CVD.


Sensor fault diagnosis for nonlinear processes with parametric uncertainties.
This paper addresses the problem of detecting, discriminating, and reconstructing sensor faults for nonlinear systems with known model structure but uncertainty in the parameters of the process. The convenience of the proposed technique lies in the fact that historical operational data and/or a priori fault information is not required to achieve accurate fault reconstruction except for fixed, short intervals. The overall fault diagnosis algorithm is composed of a series of nonlinear estimators, which estimates parameter and a fault isolation and identification filter. Parameter estimation and fault reconstruction cannot be performed accurately since faults and parametric uncertainty interact with each other. Therefore, these two tasks are performed at different time scales, where the fault diagnosis takes place at a more frequent rate than the parameter estimation. It is shown that the fault can be reconstructed under some realistic assumptions and the performance of the proposed methodology is evaluated on a simulated chemical process exhibiting nonlinear dynamic behavior.


Criteria for the selection of restoration materials.
Selection of the appropriate material for dental restoration has become more and more difficult owing to the increasing variety of restoration materials. A decision flow chart is presented to guide the treatment team (dentist and dental technician) in the selection of the restoration material. This material selection is based on the available interocclusal space, esthetic aspects (eg, brightness value or translucency of the neighboring teeth), as well as clinical evidence extracted from survival rates.


Propagation of partially coherent beams through particulate media.
When propagating through particulate media, optical beams are degraded owing to scattering. We found that the ratio between the width of the distorted beam and the width of the initial beam decreases when the spatial coherence of the incident beam is reduced. These experimental observations are well described within the paraxial approximation of the transport theory.


Relationship between Peripapillary Retinal Nerve Fiber Layer Thickness Measured by Optical Coherence Tomography and Visual Field Severity Indices.
Though there are many reports regarding the structure-function relationship in glaucoma, they are too complicated to apply to the routine clinical setting. The aim of this study was to investigate the direct relationship between peripapillary retinal nerve fiber layer (RNFL) thickness measured by optical coherence tomography (OCT) and visual field (VF) severity indices computed by standard automated perimetry. This cross-sectional comparative study included 104 glaucomatous patients and 59 healthy subjects. Peripapillary RNFL thickness was measured by spectral domain (SD) and time domain (TD) OCTs. Four glaucoma VF severity indices, including mean deviation (MD), pattern standard deviation (PSD), Collaborative Initial Glaucoma Treatment Study (CIGTS) VF score, and Advanced Glaucoma Intervention Study (AGIS) VF score, were calculated using standard automated perimetry. The Pearson's correlation coefficients (r) between the average and quadrants of peripapillary RNFL thicknesses and the four VF severity indices were calculated. In glaucomatous eyes, the r value between the average RNFL thickness measured by SD OCT and each VF severity index were 0.562, -0.514, -0.577, and -0.567 for the MD, PSD, CIGTS VF score, and AGIS VF score, respectively (all p < 0.001). Among each quadrant, the inferior RNFL thickness showed the largest r value; 0.587, -0.552, -0.613, and -0.598 for the MD, PSD, CIGTS VF score, and AGIS VF score, respectively (all p < 0.001). Measurements by TD OCT showed similar strengths of association with SD OCT. Moderate correlation was identified between peripapillary RNFL thicknesses measured by SD/TD OCT and glaucoma VF severity indices. Among each quadrant, the inferior RNFL thickness showed the greatest association with glaucoma VF severity indices. There was no significant difference according to the type of VF severity index or the type of OCTs.


Differences in the health, mental health and health-promoting behaviours of rural versus urban cancer survivors in Australia.
People affected by cancer who live in rural Australia experience inferior survival compared to their urban counterparts. This study determines whether self-reported physical and mental health, as well as health-promoting behaviours, also differ between rural and urban Australian adults with a history of cancer. Weighted, representative population data were collected via the South Australian Monitoring and Surveillance System between 1 January 2010 and 1 June 2015. Data for participants with a history of cancer (n = 4295) were analysed with adjustment for survey year, gender, age group, education, income, family structure, work status, country of birth and area-level relative socioeconomic disadvantage (SEIFA). Cancer risk factors and co-morbid physical and mental health issues were prevalent among cancer survivors regardless of residential location. In unadjusted analyses, rural survivors were more likely than urban survivors to be obese and be physically inactive. They were equally likely to experience other co-morbidities (diabetes, chronic obstructive pulmonary disease, cardiovascular disease, arthritis or osteoporosis). With adjustment for SEIFA, rural/urban differences in obesity and physical activity disappeared. Rural survivors were more likely to have trust in their communities, less likely to report high/very high distress, but equally likely to report a mental health condition, both with and without adjustment for SEIFA. There is a need for deeper understanding of the impact of relative socioeconomic disadvantage on health (particularly physical activity and obesity) in rural settings and the development of accessible and culturally appropriate interventions to address rural cancer survivors' specific needs and risk factors.


Risk Factors for Liver Cirrhosis-Related Readmissions in the Largest Ethnic Minority in United States.
There are very limited data available on 30-day readmissions for ethnic minority patients with cirrhosis. The aim of the study was to identify the risk factors for 30-day readmission in ethnic minority patients admitted for cirrhosis. We did a retrospective review of 1,373 electronic medical records of patients with cirrhosis admitted from 2009 to 2011. Several parameters including alcohol use history, discharge location and cirrhosis severity scores - model for end-stage liver disease (MELD) score and Child-Pugh-Turcotte (CPT) at first admission were assessed. Statistical analysis was done using Chi-square test and t-test for categorical and continuous variables, respectively. There were 79 patients in the readmission group (63% male, 54% Hispanics and 22% African Americans) and 104 in the no readmission group (62% male, 58% Hispanics and 24% African Americans). History of alcohol use within a month prior to admission (55% vs. 33%, P = 0.002), platelet count at discharge (89,000 vs. 124,000, P = 0.003), and discharge with more than seven medications per day (7.3 vs. 5.2, P = 0.005) were identified as risk factors for readmissions by multivariate analysis. Platelet count, active alcohol use and more than seven medications at discharge are predictors of readmission. These parameters can guide future interventions to reduce readmission rate and health care costs related to cirrhosis readmissions.


Engagement of the private pharmaceutical sector for TB control: rhetoric or reality?
Private-sector retail drug outlets are often the first point of contact for common health ailments, including tuberculosis (TB). Systematic reviews on public-private mix (PPM) interventions for TB did not perform in-depth reviews specifically on engaging retail drug outlets and related stakeholders in the pharmaceutical sector. Our objective was to better understand the extent to which the World Health Organization's (WHO) recommendation on engaging retail drug outlets has been translated into programmatic policy, strategy, and intervention in low- and middle-income countries. The study included a content analysis of global-level documents from WHO and the Stop TB Partnership in five phases. A country-level content analysis from four data sources was performed. Global-level findings were tabulated based on key messages related to engaging retail drug outlets. Country-level findings were analyzed based on four factors and tabulated. National strategic plans for TB control from 14 countries with varying TB burdens and a strong private sector were reviewed. 33 global-level documents and 77 full-text articles and Union World Lung Health conference abstracts were included for review. Based on experience of engaging retail drug outlets that has emerged since the mid-2000s, in 2011 WHO and the International Pharmaceutical Federation released a joint statement on promoting the engagement of national pharmacy associations in partnership with national TB programs. Only two of 14 countries' national strategic plans had explicit statements on the need to engage their national pharmacy professional association. The success rate of referrals from retail drug outlets who visited an approved health facility for TB screening ranged from 48% in Vietnam to 86% in Myanmar. Coverage of retail drug outlets ranged from less than 5 to 9% of the universe of retail drug outlets. For WHO's End TB Strategy to be successful, scaling up retail drug outlets to increase national coverage, at least in countries with a thriving private sector, will be instrumental in accelerating the early detection and referral of the 3 million missing TB cases. The proposed PPM pharmacy model is applicable not only for TB control but also to tackle the antimicrobial resistance crisis in these countries.


The effects of aging, physical training, and a single bout of exercise on mitochondrial protein expression in human skeletal muscle.
Aging results in a significant decline in aerobic capacity and impaired mitochondrial function. We have tested the effects of moderate physical activity on aerobic capacity and a single bout of exercise on the expression profile of mitochondrial biogenesis, and fusion and fission related genes in skeletal muscle of human subjects. Physical activity attenuated the aging-associated decline in VO2 max (p<0.05). Aging increased and a single exercise bout decreased the expression of nuclear respiratory factor-1 (NRF1), while the transcription factor A (TFAM) expression showed a strong relationship with VO(2max) and increased significantly in the young physically active group. Mitochondrial fission representing FIS1 was induced by regular physical activity, while a bout of exercise decreased fusion-associated gene expression. The expression of polynucleotide phosphorylase (PNPase) changed inversely in young and old groups and decreased with aging. The A2 subunit of cyclic AMP-activated protein kinase (AMPK) was induced by a single bout of exercise in skeletal muscle samples of both young and old subjects (p<0.05). Our data suggest that moderate levels of regular physical activity increases a larger number of mitochondrial biogenesis-related gene expressions in young individuals than in aged subjects. Mitochondrial fission is impaired by aging and could be one of the most sensitive markers of the age-associated decline in the adaptive response to physical activity.


Correlation between sleep and cognitive functions after hemispheric ischaemic stroke.
The aim of this study was to test the hypothesis of a link between sleep and cognitive functions, particularly memory and attention, after stroke. We studied 11 consecutive patients with first-ever hemispheric ischaemic stroke within eight days after symptoms onset and nine of them at least three months after stroke. Sleep EEG was recorded with a portable system. Cognitive functions were assessed using a standardized battery of tests allowing the estimation of the most relevant domains of cognition. Five age-matched healthy subjects served as controls. The patients were aged 43 +/- 12 years (18-59). In five patients stroke was right-sided and in six patients left-sided. In the acute stroke phase a correlation between attention and amounts of slow wave sleep (SWS), Rapid eye movement (REM) sleep and sleep efficiency was found. In the recovery phase verbal/figural memory and attention significantly improved in most patients. Furthermore, an association between (i) verbal/figural (non-verbal) memory and amounts of SWS, REM sleep and sleep efficiency, and between (ii) attention and sleep efficiency was observed. The results point to a link between sleep and cognitive functions and their recovery after hemispheric stroke. Further studies are needed to determine the specific nature of this link.


Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy: Dutch cardiologists and the care of mutation carriers.
Background. Patients with hypertrophic cardiomyopathy (HCM) and HCM mutation carriers are at risk of sudden cardiac death (SCD). Both groups should therefore be subject to regular cardiological testing - including risk stratification for SCD - according to international guidelines. We evaluated Dutch cardiologists' knowledge of and adherence to international guidelines on risk stratification and prevention of SCD in mutation carriers with and without manifest HCM.Methods. A questionnaire was sent to 1109 Dutch cardiologists (in training) containing case-based questions.Results. The response rate was 21%. Own general knowledge on HCM care was rated as insufficient by 63% of cardiologists. The percentage of correct answers (i.e. in agreement with international guidelines), on the case-based questions ranged from 37 to 96%, being lowest in cases with an unknown number of risk factors for SCD. A substantial portion of correct answers was based on the correct answer 'ask an expert opinion'. Significantly more correct answers were provided in cases with manifest HCM. There was little difference between the answers of cardiologists with different self-reported levels of knowledge, with different numbers of HCM patients in their practice or with different numbers of carriers without manifest HCM.Conclusion. Knowledge on risk stratification and preventive therapy was mediocre, and knowledge gaps exist, especially on HCM mutation carriers without manifest disease. Fortunately, experts are frequently asked for their opinion which might bring patient care to an adequate level. Hopefully, our results will stimulate cardiologists to follow developments in this field, thereby increasing quality of care for HCM patients and mutation carriers. (Neth Heart J 2009;17:464-9.).


Cannabinoids Reduce Extracellular Vesicle Release from HIV-1 Infected Myeloid Cells and Inhibit Viral Transcription.
Of the 37.9 million individuals infected with human immunodeficiency virus type 1 (HIV-1), approximately 50% exhibit HIV-associated neurocognitive disorders (HAND). We and others previously showed that HIV-1 viral RNAs, such as trans-activating response (TAR) RNA, are incorporated into extracellular vesicles (EVs) and elicit an inflammatory response in recipient naïve cells. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the primary cannabinoids present in cannabis, are effective in reducing inflammation. Studies show that cannabis use in people living with HIV-1 is associated with lower viral load, lower circulating CD16+ monocytes and high CD4+ T-cell counts, suggesting a potentially therapeutic application. Here, HIV-1 infected U1 monocytes and primary macrophages were used to assess the effects of CBD. Post-CBD treatment, EV concentrations were analyzed using nanoparticle tracking analysis. Changes in intracellular and EV-associated viral RNA were quantified using RT-qPCR, and changes in viral proteins, EV markers, and autophagy proteins were assessed by Western blot. Our data suggest that CBD significantly reduces the number of EVs released from infected cells and that this may be mediated by reducing viral transcription and autophagy activation. Therefore, CBD may exert a protective effect by alleviating the pathogenic effects of EVs in HIV-1 and CNS-related infections.


Safety and immunogenicity of the quadrivalent HPV vaccine in female Systemic Lupus Erythematosus patients aged 12 to 26 years.
Women with SLE have higher rates of persistent human papilloma virus (HPV) infections and precancerous lesions than healthy women. HPV vaccine is safe and effective in healthy females aged 9-26 years. There are limited data on the safety and immunogenicity of HPV vaccine in females with SLE, and none in adolescents with SLE. Our study evaluates the safety and immunogenicity of recombinant quadrivalent HPV vaccine, Gardasil, in adolescents and young women with SLE. This is a prospective, open-label study. Exclusion criteria included disease exacerbation within past 30 days; rituximab or cyclophosphamide within 6 months; pregnancy. Vaccine was administered at months 0, 2, and 6. Physical examination, SLEDAI scores and laboratory studies were performed at months 0, 2, 4, 6 and 7. Each patient's SLEDAI scores and laboratory profile in the year prior to vaccine administration were used as controls for that patient. Primary outcome measures were change in SLEDAI and mean HPV antibody titers. 27 patients, 12 to 26 years, were enrolled; 20 completed the study. Nine had mild/moderate lupus flares. Mean SLEDAI scores decreased from 6.14 pre-vaccination to 4.49 post-vaccination (p = 0.01). Of 12 patients with lupus nephritis, two experienced worsening renal function during/after the study and progressed to renal failure within 18 months of the study. Both had Class IV lupus nephritis with high chronicity scores (≥ 8) on renal biopsies performed within one year prior to study entry. Seropositivity post-vaccine was >94% for HPV 6, 11, 16 and 18. Quadrivalent HPV vaccine seems generally safe and well tolerated in this series of adolescents and young women with SLE, with no increase in mean SLEDAI scores. Progression to renal failure in two patients was most likely secondary to pre-existing severe renal chronicity and not secondary to HPV vaccination. Immunogenicity to the quadrivalent HPV vaccine was excellent, with the seropositivity rate >94% in all four HPV types.


Fiber cell denucleation in the primate lens.
To determine the morphologic and biochemical events preceding the breakdown of fiber cell nuclei in the primate lens. Monkey lens slices were labeled with fluorescent probes and optically sectioned using a confocal microscope. The distribution of nuclear histones was visualized by immunofluorescence. DNA and cellular membranes were imaged simultaneously by staining with SYTO 17 and 3,3'-dihexyloxacarbocyanine iodide, respectively. The condition of fiber cell DNA during differentiation was determined by an in situ DNA fragmentation assay. The assay was adapted to allow the detection of DNA fragments with 3'-OH or 3'-PO4 termini. Monkey lens fiber nuclei passed through distinct stages before disintegrating. In the outer cell layers, the nuclei were large, smooth, and oval-shaped with prominent nucleoli. Deeper in the lens, they had a flattened profile with whorls of membranous material and nucleic acid accumulated at one end. At this point, histone immunofluorescence was reduced and the nucleoli had a characteristic, spoked appearance. At the border of the organelle-free zone, the intracellular membranes (including the nuclear envelope) disappeared, and particulate material was released from the nuclei into the cytoplasm. This material was stained by SYTO-17 and the DNA fragmentation assay, indicating that it contained fragmented DNA with 3'-OH termini. The denucleation process in the primate lens differs from that described recently in the embryonic chicken lens. In particular, the extrusion of nuclear material and persistence of DNA-rich particles in the fiber cytoplasm are novel features. One similarity between the denucleation process in these species is the appearance of 3'-OH ends in the DNA after the loss of the nuclear membrane.


Evidence for a differential avidity model of T cell selection in the thymus.
Positive and negative selection of a lymphocytic choriomeningitis virus (LCMV) peptide-specific, H-2Db-restricted T cell clone (P14) was studied using TAP1- and TAP1+ mice transgenic for P14 T cell receptor (TCR) alpha and beta genes. Positive selection of transgenic CD8+ P14 cells was impaired in TAP1- mice. Addition of the LCMV peptide to TAP1- fetal thymic organ cultures (FTOCs) at low and high concentrations induced positive and negative selection of CD8+ P14 cells, respectively, while addition of the same peptide to TAP1+ FTOCs induced negative selection even at low concentrations. Both types of selection were peptide specific. Thus, a critical parameter that controls the fate of a thymocyte seems to be the number of TCRs engaged with complexes of peptide and major histocompatibility complex. When this number is low, positive selection occurs, and when it is high, negative selection takes place. These findings support a differential avidity model of T cell selection.


CURATE.AI: Optimizing Personalized Medicine with Artificial Intelligence.
The clinical team attending to a patient upon a diagnosis is faced with two main questions: what treatment, and at what dose? Clinical trials' results provide the basis for guidance and support for official protocols that clinicians use to base their decisions upon. However, individuals rarely demonstrate the reported response from relevant clinical trials, often the average from a group representing a population or subpopulation. The decision complexity increases with combination treatments where drugs administered together can interact with each other, which is often the case. Additionally, the individual's response to the treatment varies over time with the changes in his or her condition, whether via the indication or physiology. In practice, the drug and the dose selection depend greatly on the medical protocol of the healthcare provider and the medical team's experience. As such, the results are inherently varied and often suboptimal. Big data approaches have emerged as an excellent decision-making support tool, but their application is limited by multiple challenges, the main one being the availability of sufficiently big datasets with good quality, representative information. An alternative approach-phenotypic personalized medicine (PPM)-finds an appropriate drug combination (quadratic phenotypic optimization platform [QPOP]) and an appropriate dosing strategy over time (CURATE.AI) based on small data collected exclusively from the treated individual. PPM-based approaches have demonstrated superior results over the current standard of care. The side effects are limited while the desired output is maximized, which directly translates into improving the length and quality of individuals' lives.


Measuring the optical properties of astrophysical dust analogues: instrumentation and methods.
Dust is found throughout the universe and plays an important role for a wide range of astrophysical phenomena. In recent years, new IR facilities have provided powerful new data for understanding these phenomena. However, interpretation of these data is often complicated by a lack of complementary information about the optical properties of astronomically relevant materials. The Optical Properties of Astronomical Silicates with Infrared Techniques (OPASI-T) program at NASA's Goddard Space Flight Center is designed to provide new high-quality laboratory data from which we can derive the optical properties of astrophysical dust analogues. This program makes use of multiple instruments, including new equipment designed and built specifically for this purpose. The suite of instruments allows us to derive optical properties over a wide wavelength range, from the near-IR through the millimeter, also providing the capability for exploring how these properties depend upon the temperature of the sample. In this paper, we discuss the overall structure of the research program, describe the new instruments that have been developed to meet the science goals, and demonstrate the efficacy of these tools.


Renal responses to exercise-induced lactic acidosis.
Five healthy males performed four 30-s bouts of maximal exercise, separated by 4 min of rest, on an isokinetic cycle ergometer. Arterial blood and urine samples were taken from indwelling catheters at rest, immediately postexercise, and for 90 min of recovery. Inulin was continuously infused to measure glomerular filtration rate (GFR). Arterial plasma [Na+], [K+], and [Cl-] increased (P less than 0.05) with exercise; plasma lactate concentration ([Lac-]) increased from 1.3 +/- 0.2 to 21.0 +/- 1.0 (SE) meq/l (P less than 0.05). A significant decrease in the GFR occurred after exercise and during recovery associated with reductions in renal Na+ and K+ excretion (P less than 0.05). Renal excretion of Lac- reached a maximum of 293 +/- 79.4 mu eq.kg-1.h-1 (P less than 0.05), with Cl- excretion reaching a minimum of 4.8 +/- 0.95 mu eq.kg-1.h-1 (P less than 0.05). Urine [Lac-] was 189 +/- 25.6 meq/l, and urine [Cl-] was 6 +/- 1.7 meq/l at 30 min of recovery. There was a curvilinear relationship between urine [Cl-] and [Lac-] (r = -0.86; P less than 0.0001). Net Lac- production was estimated from arterial [Lac-] and after assuming a distribution volume. Less than 2% (13.1 meq) of the total estimated Lac- produced (678 meq) was excreted in the urine. Decreases in urine [Cl-] act to limit the fall in urine pH that accompanies increases in urine [Lac-].


Expanding whole exome resequencing into non-human primates.
Complete exome resequencing has the power to greatly expand our understanding of non-human primate genomes. This includes both a better appreciation of the variation that exists in non-human primate model species, but also an improved annotation of their genomes. By developing an understanding of the variation between individuals, non-human primate models of human disease can be better developed. This effort is hindered largely by the lack of comprehensive information on specific non-human primate genetic variation and the costs of generating these data. If the tools that have been developed in humans for complete exome resequencing can be applied to closely related non-human primate species, then these difficulties can be circumvented. Using a human whole exome enrichment technique, chimpanzee and rhesus macaque samples were captured alongside a human sample and sequenced using standard next-generation methodologies. The results from the three species were then compared for efficacy. The chimpanzee sample showed similar coverage levels and distributions following exome capture based on the human genome as the human sample. The rhesus macaque sample showed significant coverage in protein-coding sequence but significantly less in untranslated regions. Both chimpanzee and rhesus macaque showed significant numbers of frameshift mutations compared to self-genomes and suggest a need for further annotation. Current whole exome resequencing technologies can successfully be used to identify coding-region variation in non-human primates extending into old world monkeys. In addition to identifying variation, whole exome resequencing can aid in better annotation of non-human primate genomes.


Economic evaluation of nebulized magnesium sulphate in acute severe asthma in children.
The aim of this study was to estimate the cost-effectiveness of nebulized magnesium sulphate (MgSO4) in acute asthma in children from the perspective of the UK National Health Service and personal social services. An economic evaluation was conducted based on evidence from a randomized placebo controlled multi-center trial of nebulized MgSO4 in severe acute asthma in children. Participants comprised 508 children aged 2-16 years presenting to an emergency department or a children's assessment unit with severe acute asthma across thirty hospitals in the United Kingdom. Children were randomly allocated to receive nebulized salbutamol and ipratropium bromide mixed with either 2.5 ml of isotonic MgSO4 or 2.5 ml of isotonic saline on three occasions at 20-min intervals. Cost-effectiveness outcomes were constructed around the Yung Asthma Severity Score (ASS) after 60 min of treatment; whilst cost-utility outcomes were constructed around the quality-adjusted life-year (QALY) metric. The nonparametric bootstrap method was used to present cost-effectiveness acceptability curves at alternative cost-effectiveness thresholds for either: (i) a unit reduction in ASS; or (ii) an additional QALY. MgSO4 had a 75.1 percent probability of being cost-effective at a GBP 1,000 (EUR 1,148) per unit decrement in ASS threshold, an 88.0 percent probability of being more effective (in terms of reducing the ASS) and a 36.6 percent probability of being less costly. MgSO4 also had a 67.6 percent probability of being cost-effective at a GBP 20,000 (EUR 22,957) per QALY gained threshold, an 8.5 percent probability of being more effective (in terms of generating increased QALYs) and a 69.1 percent probability of being less costly. Sensitivity analyses showed that the results of the economic evaluation were particularly sensitive to the methods used for QALY estimation. The probability of cost-effectiveness of nebulized isotonic MgSO4, given as an adjuvant to standard treatment of severe acute asthma in children, is less than 70 percent across accepted cost-effectiveness thresholds for an additional QALY.


Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition.
Mutational heterogeneity must be taken into account when reconstructing evolutionary histories, calibrating molecular clocks, and predicting links between genes and disease. Selective pressures and various DNA transactions have been invoked to explain the heterogeneous distribution of genetic variation between species, within populations, and in tissue-specific tumors. To examine relationships between such heterogeneity and variations in leading- and lagging-strand replication fidelity and mismatch repair, we accumulated 40,000 spontaneous mutations in eight diploid yeast strains in the absence of selective pressure. We found that replicase error rates vary by fork direction, coding state, nucleosome proximity, and sequence context. Further, error rates and DNA mismatch repair efficiency both vary by mismatch type, responsible polymerase, replication time, and replication origin proximity. Mutation patterns implicate replication infidelity as one driver of variation in somatic and germline evolution, suggest mechanisms of mutual modulation of genome stability and composition, and predict future observations in specific cancers.


Sequelae in 145 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR).
Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe adverse drug reaction caused by specific drug. It is characterized by visceral organ involvement and reactivation of various human herpesviruses. Although sporadic reports have documented certain conditions that appear after the resolution of DIHS/DRESS, little information is available on sequelae after resolution of DIHS/DRESS in a large patient population. The Asian Research Committee on Severe Cutaneous Adverse Reactions, comprised of doctors from Japan and Taiwan, conducted a survey on sequelae and deterioration of the underlying disease in patients with DIHS/DRESS. This was achieved by directly interviewing patients who had been followed-up by experts or through a questionnaire mailed to patients. Questions were asked about new onset cardiovascular disease, collagen disease or autoimmune disease, gastrointestinal disease, renal disease, respiratory disease, neoplasms, and other diseases such as herpes zoster and diabetes mellitus, as well as deterioration of the underlying disease. A total of 145 patients were analyzed in this study. The following newly developed diseases after recovery from DIHS/DRESS were observed: Graves' disease (n = 2), Hashimoto's disease (n = 3), painless thyroiditis (n = 2), fulminant type 1 diabetes mellitus (n = 5), and infectious diseases (n = 7). Several DIHS/DRESS patients with pre-existing renal dysfunction required lifelong hemodialysis. DIHS/DRESS is a condition that increases the risk of new onset of disease. Long-term observation of DIHS/DRESS can provide an opportunity to investigate substantial diseases from onset to the full-blown stage. Patients with DIHS/DRESS require careful long-term follow-up.


Modification of TiO2 for enhanced surface properties: finite Ostwald ripening by a microwave hydrothermal process.
The effect of microwave modification of colloidal TiO2 suspensions under extended periods of treatment is presented. The nanoparticulate TiO2 is compared and contrasted to similar convection hydrothermally treated TiO2 and a commercial titania product, namely Degussa P25. Microwave-treated samples were analyzed by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and Raman spectroscopy to determine their physicochemical characteristics. Comparative surface area analyses were performed by N2 adsorption and calculated from a Brunauer-Emmett-Teller (BET) isotherm. The complementary techniques of XRD and TEM showed good correlation between observed and calculated particle sizes (by application of the Scherrer equation), with the material being highly crystalline anatase TiO2, as identified by XRD and Raman. This investigation identified that extended periods of microwave hydrothermal treatment do not greatly enhance the crystallinity and primary grain size. Treatment of >180 min has a negative effect on crystallite growth; however, treatment up to this time had a significant effect on the material's surface area. The limiting regime of Ostwald ripening for hydrothermal treatment is discussed in relation to the mechanism of microwave treatment, that is, rapid heating to temperature and extremely rapid rates of crystallization. The effect of these property modifications are further discussed in relation to photocatalytic and photoelectrochemical applications of TiO2 nanoparticles.


A comparison of the effectiveness of low-, moderate- and high-dose ultrasound therapy applied in the treatment of myofascial pain syndrome.
This study aimed to compare and evaluate the effects of ultrasound (US) treatment applied at low-, medium- and high-power-pain threshold (HPPT) doses to trigger points in the treatment of myofascial pain syndrome (MPS). The study comprised 61 (40 female and 21 male) patients diagnosed with MPS, aged between 18 and 60 years. The patients were randomly allocated to three groups for the US application at different dosages. Group I patients received treatment of medium-dose US (1.5 Watt/cm(2)), Group II received HPPT US, and Group III received low-dose US (0.5 W/cm(2)). The patients were evaluated pre-treatment and 3 weeks after treatment in respect of visual analogue scale (VAS) scores, number of trigger points (NTP), pressure pain threshold (PPT), Range of Tragus-Acromioclavicular joint (RT-AJ) and neck pain disability scores (NPDS). A significant improvement was determined after treatment in all scores except PPT in Group I, in all scores in Group II, and only in the VAS score in Group III. When the groups were compared post-treatment in respect of improvement in NTP, VAS, RT-AJ and NPDS scores, Group II showed significant superiority over Group I, and Group I was determined to have significant superiority over Group III in respect of VAS, RT-AJ and NPDS scores (p < 0.05). In the treatment of MPS, US therapy at HPPT dose can be considered as an alternative therapy method, which is more economical and more effective than low-dose and conventional US therapy.


Fas/Fas ligand deficiency results in altered localization of anti-double-stranded DNA B cells and dendritic cells.
Autoantibodies directed against dsDNA are found in patients with systemic lupus erythematosus as well as in mice functionally deficient in either Fas or Fas ligand (FasL) (lpr/lpr or gld/gld mice). Previously, an IgH chain transgene has been used to track anti-dsDNA B cells in both nonautoimmune BALB/c mice, in which autoreactive B cells are held in check, and MRL-lpr/lpr mice, in which autoantibodies are produced. In this study, we have isolated the Fas/FasL mutations away from the autoimmune-prone MRL background, and we show that anti-dsDNA B cells in Fas/FasL-deficient BALB/c mice are no longer follicularly excluded, and they produce autoantibodies. Strikingly, this is accompanied by alterations in the frequency and localization of dendritic cells as well as a global increase in CD4 T cell activation. Notably, as opposed to MRL-lpr/lpr mice, BALB-lpr/lpr mice show no appreciable kidney pathology. Thus, while some aspects of autoimmune pathology (e.g., nephritis) rely on the interaction of the MRL background with the lpr mutation, mutations in Fas/FasL alone are sufficient to alter the fate of anti-dsDNA B cells, dendritic cells, and T cells.


Long-range conserved non-coding SHOX sequences regulate expression in developing chicken limb and are associated with short stature phenotypes in human patients.
Defects in long-range regulatory elements have recently emerged as previously underestimated factors in the genesis of human congenital disorders. Léri-Weill dyschondrosteosis is a dominant skeletal malformation syndrome caused by mutations in the short stature homeobox gene SHOX. We have analysed four families with Léri-Weill dyschondrosteosis with deletions in the pseudoautosomal region but still with an intact SHOX coding region. Using fluorescence in situ hybridization and single nucleotide polymorphism studies, we identified an interval of approximately 200 kb that was deleted in all tested affected family members but retained in the unaffected members and in 100 control individuals. Comparative genomic analysis of this interval revealed eight highly conserved non-genic elements between 48 and 215 kb downstream of the SHOX gene. As mice do not have a Shox gene, we analysed the enhancer potential in chicken embryos using a green fluorescent protein reporter construct driven by the beta-globin promoter, by in ovo electroporation of the limb bud. We observed cis-regulatory activity in three of the eight non-genic elements in the developing limbs arguing for an extensive control region of this gene. These findings are consistent with the idea that the deleted region in the affected families contains several distinct elements that regulate Shox expression in the developing limb. Furthermore, the deletion of these elements in humans generates a phenotype apparently undistinguishable to those patients identified with mutations in the SHOX coding region and, for the first time, demonstrates the potential of an in vivo assay in chicken to monitor putative enhancer activity in relation to human disease.


Safety and Benefit of Transesophageal Echocardiography in Liver Transplant Surgery: A Position Paper From the Society for the Advancement of Transplant Anesthesia (SATA).
More anesthesiologists are routinely using transesophageal echocardiography (TEE) during liver transplant surgery, but the effects on patient outcome are unknown. Transplant anesthesiologists are therefore uncertain if they should undergo additional training and adopt TEE. In response to these clinical questions, the Society for the Advancement of Transplant Anesthesia appointed experts in liver transplantation and who are certified in TEE to evaluate all available published evidence on the topic. The aim was to produce a summary with greater explanatory power than individual reports to guide transplant anesthesiologists in their decision to use TEE. An exhaustive search recovered 51 articles of uncontrolled clinical observations. Topics chosen for this study were effectiveness and safety because they were a major or minor topic in all articles. The pattern of clinical use was a common topic and was included to provide contextual information. Summarized observations showed effectiveness as the ability to make a new and unexpected diagnosis and to direct the choice of clinical management. These were reported in each stage of liver transplant surgery. There were observations that TEE facilitated rapid diagnosis of life-threatening conditions difficult to identify with other types of monitoring commonly used in the operating room. Real-time diagnosis by TEE images made anesthesiologists confident in their choice of interventions, especially those with a high risk of complications such as use of anticoagulants for intracardiac thrombosis. The summarized observations in this systematic review suggest that TEE is an effective form of monitoring with a safety profile similar to that in cardiac surgery patients.


Structural preferences of gas-phase M2TMP monomers upon sequence variations.
The conformations of a number of M2TMP(22-46) sequence variants have been investigated using ion mobility spectrometry (IMS). Substantial conformational changes were evidenced by IMS upon the variation of a single amino acid in the peptide sequence, with two main drift time signatures. Replica-exchange molecular dynamics simulations were used to help assign the structures of the different identified conformers. Even though one-on-one agreement with experiment was found for only two variants, the simulations generally confirmed the existence of two structural families. Based on these results, most of the triply protonated variants, including the wild-type peptide, were found to display collision cross sections in agreement with compact conformations in the gas phase, whereas they tend to form extended α-helices in the condensed phase, as confirmed by circular dichroism and previously reported NMR measurements. The destabilization of α-helices in vacuo upon amino acid substitution is interpreted as being driven by the solvation pattern of the charges.


Optimizing Online Suicide Prevention: A Search Engine-Based Tailored Approach.
Search engines are increasingly used to seek suicide-related information online, which can serve both harmful and helpful purposes. Google acknowledges this fact and presents a suicide-prevention result for particular search terms. Unfortunately, the result is only presented to a limited number of visitors. Hence, Google is missing the opportunity to provide help to vulnerable people. We propose a two-step approach to a tailored optimization: First, research will identify the risk factors. Second, search engines will reweight algorithms according to the risk factors. In this study, we show that the query share of the search term "poisoning" on Google shows substantial peaks corresponding to peaks in actual suicidal behavior. Accordingly, thresholds for showing the suicide-prevention result should be set to the lowest levels during the spring, on Sundays and Mondays, on New Year's Day, and on Saturdays following Thanksgiving. Search engines can help to save lives globally by utilizing a more tailored approach to suicide prevention.


Integrating Universal Design and Accessibility into Computer Science Curricula - A Review of Literature and Practices in Europe.
The absence of accessibility in many ICT systems and products indicates insufficient accessibility competence among designers, developers and project managers. Higher education institutions play an important role in raising awareness and competence and in preparing universal design and digital accessibility specialists. Although many universities are teaching accessibility as part of the biomedical, special education and disability studies programmes, few provide accessibility education in technical specialisations such as computer science. By combining literature review and manual search and inspection we aim at investigating the state of the art in integrating universal design and digital accessibility into the curricula of computer sciences-related programmes.


Expression of a class 1 hemoglobin gene and production of nitric oxide in response to symbiotic and pathogenic bacteria in Lotus japonicus.
Symbiotic nitrogen fixation by the collaboration between leguminous plants and rhizobia is an important system in the global nitrogen cycle, and some molecular aspects during the early stage of host-symbiont recognition have been revealed. To understand the responses of a host plant against various bacteria, we examined expression of hemoglobin (Hb) genes and production of nitric oxide (NO) in Lotus japonicus after inoculation with rhizobia or plant pathogens. When the symbiotic rhizobium Mesorhizobium loti was inoculated, expression of LjHb1 and NO production were induced transiently in the roots at 4 h after inoculation. In contrast, inoculation with the nonsymbiotic rhizobia Sinorhizobium meliloti and Bradyrhizobium japonicum induced neither expression of LjHb1 nor NO production. When L. japonicus was inoculated with plant pathogens (Ralstonia solanacearum or Pseudomonas syringae), continuous NO production was observed in roots but induction of LjHb1 did not occur. These results suggest that modulation of NO levels and expression of class 1 Hb are involved in the establishment of the symbiosis.


Elevated intraocular pressure and optic nerve injury models in the rat.
Models of experimentally elevated intraocular pressure in rats provide valuable opportunities to discover and study mechanisms of pressure-induced optic nerve damage. The structure and vasculature of the rat optic nerve head have several anatomic similarities and differences from the primate that allow useful comparisons and insights into human glaucoma. Specifically, the ultrastructural relationship between astrocytes, retinal ganglion cell axons and the connective tissues of the optic nerve head appear quite similar to the primate, and have a high potential for revealing cellular mechanisms of axonal injury. Three widely used models of creating elevated IOP in rats exist. However, they are not all equivalent and appear to differ in the relationship they exhibit between the level of pressure and extent of optic nerve damage. This indicates that these models may differ in the mechanisms by which they produce elevated eye pressure. All of these models are amenable to a variety of methods for evaluating damage. These include objective and subjective histologic assessment of the optic nerve, counting cells in the retinal ganglion cell layer of the retina and the use of retinal whole mounts to count retinal ganglion cells that have been back-labeled with dye applied to the superior colliculus. In the decade since their introduction, these versatile models have provided important insights into mechanisms of pressure-induced optic nerve damage using sensitive molecular biology techniques. They have also allowed the evaluation of several potential strategies for neuroprotection in glaucoma, ranging from currently available drugs to gene transfer studies.


[National Action Plan Health Literacy: Need, Objective and Content].
In recent years, studies on health literacy of the population have been conducted in many countries. Most of them show that health literacy levels are worse than expected and that large parts of the population have low health literacy levels. National strategies and action plans to promote health literacy have been developed in many countries to address these results. Following these examples, a National Action Plan on Health Literacy was also developed for Germany. A panel of 15 experts was involved in the 2-year development process. Based on an analysis of available literature on health literacy and existing action plans, the concept, objectives and priorities of the action plan were defined, and recommendations were developed. The National Action Plan on Health Literacy formulates recommendations in the fields of living environments, the healthcare system, chronic illness, and research.


Ligating properties of anionic Fischer-type carbene complexes, [(CO)(5)M[double bond, length as m-dash]C(X)Y](-).
With the simplest of anionic Fischer-type carbene complexes acting as ligands, Cp(2)Zr(Cl){OCMe}M(CO)(5) compounds (M = Cr or W) promote alpha-olefin oligomerization and polymerization in the presence of MAO. Attaching an N-heterocyclic ring to the carbene carbon atom in similar precursors, allows a variety of hard metal ions and fragments to be captured by external bidentate coordination. The outcome of the attachment of a phosphorus or sulfur functionality to an alpha-carbon of an O-anionic carbene is formation of a bidentate ligand and then internal four-membered carbene-heteroatom chelate formation. alpha-Deprotonated carbene complexes are also precursors for remote, one-N, six-membered carbene complexes of various metals whereas alpha-C-, alpha-N- or alpha-O-deprotonated as well as beta-deprotonated Fischer-type carbene complexes display unique synthon properties towards Ph(3)PAu(+) and partake in unusual ensuing coordination of liberated group 6 metal carbonyl moieties to form dinuclear products.


Quick and dirty? A systematic review of the use of rapid ethnographies in healthcare organisation and delivery.
The ability to capture the complexities of healthcare practices and the quick turnaround of findings make rapid ethnographies appealing to the healthcare sector, where changing organisational climates and priorities require actionable findings at strategic time points. Despite methodological advancement, there continue to be challenges in the implementation of rapid ethnographies concerning sampling, the interpretation of findings and management of field research. The purpose of this review was to explore the benefits and challenges of using rapid ethnographies to inform healthcare organisation and delivery and identify areas that require improvement. This was a systematic review of the literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We used the Mixed Methods Appraisal Tool to assess the quality of the articles. We developed the search strategy using the Population, Intervention, Comparison, Outcomes, Settingframework and searched for peer-reviewed articles in MEDLINE, CINAHL PLUS, Web of Science and ProQuest Central. We included articles that reported findings from rapid ethnographies in healthcare contexts or addressing issues related to health service use. 26 articles were included in the review. We found an increase in the use of rapid ethnographies in the last 2‰years. We found variability in terminology and developed a typology to clarify conceptual differences. The studies generated findings that could be used to inform policy and practice. The main limitations of the studies were: the poor quality of reporting of study designs, mainly data analysis methods, and lack of reflexivity. Rapid ethnographies have the potential to generate findings that can inform changes in healthcare practices in a timely manner, but greater attention needs to be paid to the reflexive interpretation of findings and the description of research methods. CRD42017065874.


A phenomenological study of business graduates' employment experiences in the changing economy.
This study explores the perspectives of business college graduates, how technology has shaped the structures of their jobs, and the role of non-technical skills as they navigate the changing career path. Three overlapping themes emerged from the data analysis: (1) influence of increased technology capabilities on job structures and careers; (2) participation in job-related training and formal education as means of adapting to the new work environment; and (3) the role of non-technical skills in the workplace amidst the intensification of technology change. This research provides higher education practitioners and labor market researchers qualitative perspectives on work structure changes.


Mechanisms of permanent loss of olfactory receptor neurons induced by the herbicide 2,6-dichlorobenzonitrile: effects on stem cells and noninvolvement of acute induction of the inflammatory cytokine IL-6.
We explored the mechanisms underlying the differential effects of two olfactory toxicants, the herbicide 2,6-dichlorobenzonitrile (DCBN) and the anti-thyroid drug methimazole (MMZ), on olfactory receptor neuron (ORN) regeneration in mouse olfactory epithelium (OE). DCBN, but not MMZ, induced inflammation-like pathological changes in OE, and DCBN increased interleukin IL-6 levels in nasal-wash fluid to much greater magnitude and duration than did MMZ. At 24h after DCBN injection, the population of horizontal basal cells (HBCs; reserve, normally quiescent OE stem cells) lining the DMM became severely depleted as some of them detached from the basal lamina, and sloughed into the nasal cavity along with the globose basal cells (GBCs; heterogeneous population of stem and progenitor cells), neurons, and sustentacular cells of the neuroepithelium. In contrast, the layer of HBCs remained intact in MMZ-treated mice, as only the mature elements of the neuroepithelium were shed. Despite the respiratory metaplasia accompanying the greater severity of the DCBN lesion, residual HBCs that survived intoxication were activated by the injury and contributed to the metaplastic respiratory epithelium, as shown by tracing their descendants in a K5CreEr(T2)::fl(stop)TdTomato strain of mice in which recombination causes HBCs to express TdTomato in advance of the lesion. But, contrary to published observations with MMZ, the HBCs failed to form ORNs. A role for IL-6 in suppressing ORN regeneration in DCBN-treated mice was rejected by the failure of the anti-inflammatory drug dexamethasone to prevent the subsequent respiratory metaplasia in the DMM, suggesting that other factors lead to HBC neuro-incompetence.


Effect of twice-daily oral administration of a chondroitin sulfate-containing supplement on urine chondroitin sulfate concentrations in dogs.
To quantify the magnitude and duration of changes in urine chondroitin sulfate concentration (uCS) as a result of oral administration of a chondroitin sulfate-containing supplement in dogs. 8 healthy privately owned dogs. A urine sample was collected from each dog via cystocentesis on day 1; free-catch midstream urine samples were collected once daily on days 2 through 5. Pretreatment uCS was established from those samples. Each dog then received a chondroitin sulfate-containing supplement (20 to 30 mg/kg, PO, q 12 h) for 8 days (on days 7 through 14). Urine samples were collected on days 8 through 12 and day 15. For each sample, uCS was quantified by liquid chromatography-tandem mass spectrometry. Variable urine concentration was accounted for by dividing the uCS by urine creatinine concentration (uCrea) to determine the uCS:uCrea ratio. Pretreatment uCS:uCrea ratios were compared with treatment uCS:uCrea ratios to calculate the fold change in uCS after supplement administration. Among the study dogs, oral administration of the chondroitin sulfate-containing supplement resulted in a 1.9-fold increase in the median uCS:uCrea ratio. Data obtained on days 8 through 12 and day 15 indicated that the daily increase in uCS remained consistent and was not additive. Results indicated that oral administration of supplemental chondroitin sulfate to dogs modestly increased uCS within 24 hours; however, subsequent supplement administration did not have an additive effect. A potential therapeutic benefit of persistently increased uCS in preventing recurrent urinary tract infections in dogs warrants investigation.


[Effect of combined use of hyperbaric oxygenation and alpha-tocopherol on the contractile function and various components of the antioxidant system of the heart after adrenaline lesioning].
A session of hyperbaric oxygenation (HBO) at 2.5 at. abs. conducted for one hour in rabbits with adrenalin heart affection (AHA) immediately after adrenalin administration prevented a decrease in the cardiac contractile function usually developing within two hours after AHA. On the third day of the follow up, rabbits with AHA receiving daily HBO displayed a decrease in the pump and contractile functions as well as in superoxide dismutase (SOD) activity and the antioxidant activity (AOA) of the left ventricle lipids. Combination of HBO sessions with the intra-muscular administration of alpha-tocopherol (50 mg/kg) made the decrease in SOD activity less pronounced and prevented both the fall in lipid AOA and the depression of the heart contractile and pump functions on the third day following AHA. It is suggested that the combined use of HBO and substances increasing the potency of the cell antioxidation system may become one of the principles of reducing HBO side effects and of expanding the potentialities of HBO in treating ischemic and adrenergic heart impairments.


Simultaneous Photonic and Excitonic Coupling in Spherical Quantum Dot Supercrystals.
Semiconductor nanocrystals, or quantum dots (QDs), simultaneously benefit from inexpensive low-temperature solution processing and exciting photophysics, making them the ideal candidates for next-generation solar cells and photodetectors. While the working principles of these devices rely on light absorption, QDs intrinsically belong to the Rayleigh regime and display optical behavior limited to electric dipole resonances, resulting in low absorption efficiencies. Increasing the absorption efficiency of QDs, together with their electronic and excitonic coupling to enhance charge carrier mobility, is therefore of critical importance to enable practical applications. Here, we demonstrate a general and scalable approach to increase both light absorption and excitonic coupling of QDs by fabricating hierarchical metamaterials. We assemble QDs into crystalline supraparticles using an emulsion template and demonstrate that these colloidal supercrystals (SCs) exhibit extended resonant optical behavior resulting in an enhancement in absorption efficiency in the visible range of more than 2 orders of magnitude with respect to the case of dispersed QDs. This successful light trapping strategy is complemented by the enhanced excitonic coupling observed in ligand-exchanged SCs, experimentally demonstrated through ultrafast transient absorption spectroscopy and leading to the formation of a free biexciton system on sub-picosecond time scales. These results introduce a colloidal metamaterial designed by self-assembly from the bottom up, simultaneously featuring a combination of nanoscale and mesoscale properties leading to simultaneous photonic and excitonic coupling, therefore presenting the nanocrystal analogue of supramolecular structures.


Use of S-[2,3-bispalmitoyiloxy-(2R)-propyl]-R-cysteinyl-amido-monomethoxy polyethylene glycol as an adjuvant improved protective immunity associated with a DNA vaccine encoding Cu,Zn superoxide dismutase of Brucella abortus in mice.
This study was conducted to evaluate the immunogenicity and protective efficacy of a DNA vaccine encoding Brucella abortus Cu,Zn superoxide dismutase (SOD) using the Toll-like receptor 2/6 agonist S-[2,3-bispalmitoyiloxy-(2R)-propyl]-R-cysteinyl-amido-monomethoxy polyethylene glycol (BPPcysMPEG) as an adjuvant. Intranasal coadministration of BPPcysMPEG with a plasmid carrying the SOD-encoding gene (pcDNA-SOD) into BALB/c mice elicited antigen-specific humoral and cellular immune responses. Humoral responses were characterized by the stimulation of IgG2a and IgG1 and by the presence of SOD-specific secretory IgA in nasal and bronchoalveolar lavage fluids. Furthermore, T-cell proliferative responses and increased production of gamma interferon were also observed upon splenocyte restimulation with recombinant SOD. Cytotoxic responses were also stimulated, as demonstrated by the lysis of RB51-SOD-infected J774.A1 macrophages by cells recovered from immunized mice. The pcDNA-SOD/BPPcysMPEG formulation induced improved protection against challenge with the virulent strain B. abortus 2308 in BALB/c mice over that provided by pcDNA-SOD, suggesting the potential of this vaccination strategy against Brucella infection.


Haploidentical BMT for severe aplastic anemia with intensive GVHD prophylaxis including posttransplant cyclophosphamide.
Severe aplastic anemia (SAA) is a stem cell disorder often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis. Outcomes of related HLA-haploidentical (haplo) donors after reduced-intensity conditioning with intensive graft-versus-host disease (GVHD) prophylaxis including posttransplantation cyclophosphamide are presented here from 37 SAA, 20 relapsed/refractory (R/R), and 17 treatment-naïve (TN) SAA patients. Median follow-up is 32 months (90% confidence interval [CI], 29-44). The median age was 25 (range, 4-69) years. The median time to neutrophil recovery was 17 days (range, 15-88). Four of 37 patients (11%) experienced graft failure (GF). There was 1 primary GF of 20 patients in the R/R group and 3 of 17 in the TN group at 200 cGy (1 primary, 2 secondary), but none in the 10 patients who received 400 cGy total body irradiation. Two patients with GF succumbed to infection and 2 were rescued with second haplo BMT. The overall survival for all patients is 94% (90% CI, 88-100) at 1 and 2 years. The cumulative incidence of grade II-IV acute GVHD at day 100 is 11%. The cumulative index of chronic GVHD at 2 years is 8%. Similar results were seen in 10 SAA patients who received the identical nonmyeloablative regimen with posttransplant cyclophosphamide but matched donor transplants. Haplo BMT with posttransplant cyclophosphamide represents a potential cure in SAA, with all 20 R/R currently alive, disease-free, and with no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates, but an increase in total body irradiation dose to 400 cGy was associated with durable engraftment without greater early toxicity. Nonmyeloablative haplo BMT in TN SAA could lead to a paradigm shift, such that essentially all patients can proceed quickly to safe, curative BMT. These trials were registered at www.cincialtrials.gov as #NCT02224872) and #NCT02833805.


Inhibition of Trypanosoma cruzi proline racemase affects host-parasite interactions and the outcome of in vitro infection.
Proline racemase is an important enzyme of Trypanosoma cruzi and has been shown to be an effective mitogen for B cells, thus contributing to the parasite's immune evasion and persistence in the human host. Recombinant epimastigote parasites overexpressing TcPRAC genes coding for proline racemase present an augmented ability to differentiate into metacyclic infective forms and subsequently penetrate host-cells in vitro. Here we demonstrate that both anti T. cruzi proline racemase antibodies and the specific proline racemase inhibitor pyrrole-2-carboxylic acid significantly affect parasite infection of Vero cells in vitro. This inhibitor also hampers T. cruzi intracellular differentiation.


High prevalence of vitamin D insufficiency and its association with obesity and metabolic syndrome among Malay adults in Kuala Lumpur, Malaysia.
Vitamin D status, as indicated by 25-hydroxyvitamin D is inversely associated with adiposity, glucose homeostasis, lipid profiles, and blood pressure along with its classic role in calcium homeostasis and bone metabolism. It is also shown to be inversely associated with metabolic syndrome and cardiovascular diseases in western populations. However, evidence from the Asian population is limited. Therefore, we aim to study the prevalence of vitamin D insufficiency (< 50 nmol/L) and the association of 25-hydroxyvitamin D with metabolic risk factors among an existing Malay cohort in Kuala Lumpur. This is an analytical cross sectional study. A total of 380 subjects were sampled and their vitamins D status (25-hydroxyvitamin D), fasting blood glucose, full lipid profile were assessed using venous blood. Systolic and diastolic blood pressure, weight, height and waist circumference were measured following standard protocols. Socio-demographic data such as sex, age, smoking status etc were also collected. Data was analysed using t-test, chi-square test, General Linear Model and multiple logistic regression. Females made up 58% of the sample. The mean age of respondents was 48.5 (SD 5.2) years. Females had significantly lower mean Vitamin D levels (36.2; 95% CI: 34.5, 38.0 nmol/L) compared to males (56.2; 95% CI: 53.2, 59.2 nmol/L). Approximately 41% and 87% of males and females respectively had insufficient (< 50 nmol/L) levels of 25-hydroxyvitamin D (p < 0.001). The prevalence of Metabolic Syndrome for the whole sample was 38.4 (95% CI: 33.5, 43.3)%. In the multivariate model (adjusted for age, sex, abdominal obesity, HDL-cholesterol, diastolic blood pressure), insufficient Vitamin D status was significantly associated with 1-year age increments (OR: 0.93; 95% CI: 0.88, 0.98), being female (OR: 8.68; 95% CI: 5.08, 14.83) and abdominal obesity (OR: 2.57; 95% CI: 1.51, 4.39). Respondents with insufficient vitamin D were found to have higher odds of having Metabolic Syndrome (OR: 1.73; 95% CI: 1.02, 2.92) after adjusting for age and sex. Our results highlight the high prevalence of vitamin D insufficiency among Malay adults in Kuala Lumpur. Vitamin D insufficiency is independently associated with younger age, female sex and greater abdominal obesity. Vitamin D insufficiency is also associated with Metabolic Syndrome.


Complete nucleotide sequence of the prophage VT1-Sakai carrying the Shiga toxin 1 genes of the enterohemorrhagic Escherichia coli O157:H7 strain derived from the Sakai outbreak.
Shiga toxins 1 and 2 (Stx1 and Stx2) are encoded by prophages lysogenized in enterohemorrhagic Escherichia coli (EHEC) O157:H7 strains. Lytic growth of the phage particles carrying the stx1 genes (stx1A and stx1B) of the EHEC O157:H7 strain RIMD 0509952, which was derived from the Sakai outbreak in 1996 in Japan, was induced after treatment with mitomycin C, but the plaque formation of the phage was not detected. We have determined the complete nucleotide sequence of the prophage VT1-Sakai. The integration site of the prophage was identified within the yehV gene at 47.7 min on the chromosome. The stx1 genes were downstream of the Q gene in the prophage genome, suggesting that their expression was regulated by the Q protein, the regulator of the late gene expression of the phage, which is similar to that of the stx1 or stx2 genes carried by the lambdoid phages reported previously. The sequences of the N gene and its recognition sites, nutL and nutR, were not homologous to those of the phages carrying the stx genes thus far reported, but they were very similar to those of bacteriophage phi21. The sequences of the repressor proteins, CI and Cro, that regulate expression of the early genes had low similarities with those of the known repressors of other phages, and their operator sequences were different from any sequence reported. These data suggest that multiple genetic recombination among bacteriophages with different immunities took place to generate the prophage VT1-Sakai. Comparison between the sequences of VT1-Sakai and lambda suggests that the ancestor of VT1-Sakai was produced by illegitimate excision, like lambda gal and bio phages.


Increased physical activity in abdominally obese women through support for changed commuting habits: a randomized clinical trial.
Abdominally obese women can reduce their health risk through regular physical activity. There is, however, little evidence on the effectiveness of interventions that promote physical activity long-term, such as cycling and walking to and from work. This intervention focused on physically active commuting (cycling and walking) in middle-aged (30-60 years), abdominally obese (waist circumference > or = 88 cm) women (n=120), recruited by newspaper advertisement. The intervention group was a moderate-intensity programme with physician meetings, physical activity prescriptions, group counselling and bicycles. The control group was a low-intensity group support programme with pedometers. We used a randomized, controlled, 2-armed design with 18 months duration and intention-to-treat analysis (data collection 2005-2006). Treatment success was defined as bicycling > or = 2 km/d (primary) or walking 10,000 steps per day (secondary). At baseline, mean (s.d.) age was 48.2 years (7.4), waist circumference 103.8 cm (7.8), walking 8471 steps per day (2646), bicycling 0 km per day. Attrition at 18 months was 10% for the intervention group and 25% in the control group (P=0.03). The intervention group was more likely to achieve treatment success for cycling than controls: 38.7 vs 8.9% (odds ratio (OR)=7.8 (95% confidence interval=4.0 to 15.0, P<0.001)), but with no difference for compliance with the walking recommendation: 45.7 vs 39.3% (OR=1.2 (95% CI=0.7 to 2.0, P=0.50)). Commuting by car and public transport were reduced by 34% (P<0.01) and 37% (P<0.001), respectively, with no differences between groups. Both groups attained similar waist reductions (-2.1 and -2.6 cm, P=0.72). Abdominally obese women can increase PA long-term through moderate-intensity behavioural support aimed at changing commuting habits.


Advice to walk after meals is more effective for lowering postprandial glycaemia in type 2 diabetes mellitus than advice that does not specify timing: a randomised crossover study.
Regular physical activity is a cornerstone of diabetes management. We conducted a study to evaluate whether specifying the timing of walking in relation to meals enhances the benefits conferred by current physical activity guidelines. A total of 41 adults with type 2 diabetes mellitus (mean ± SD age 60 ± 9.9 years; mean diabetes duration 10 years) participated in this randomised, crossover study. Randomisation was by a computer-generated protocol. For periods of 2 weeks, advice to walk 30 min each day was compared with advice to walk for 10 min after each main meal. Both sets of advice met current physical activity guidelines for people with type 2 diabetes mellitus. Physical activity was measured by accelerometry over the full intervention, and glycaemia was measured using continuous glucose monitoring in 5 min intervals over 7 days. The primary outcome of postprandial glycaemia was assessed during the 3 h after a meal by the incremental area under the blood glucose curve (iAUC). The iAUC was significantly lower when participants walked after meals compared with on a single daily occasion (ratio of geometric means 0.88, 95% CI 0.78, 0.99). The improvement was particularly striking after the evening meal (0.78, 95% CI 0.67, 0.91) when the most carbohydrate was consumed and sedentary behaviours were highest. One participant died during the 30 day washout period between interventions, but participation in this study was not judged to contribute to this unfortunate event. The benefits relating to physical activity following meals suggest that current guidelines should be amended to specify post-meal activity, particularly when meals contain a substantial amount of carbohydrate. ACTRN12613000832774 FUNDING: : This study was supported by grants from the University of Otago and the New Zealand Artificial Limb Service. Glycated albumin reagents were provided by Asahi Kasei.


Segmentation of 3D holographic images using bivariate jointly distributed region snake.
In this paper, we describe the bivariate jointly distributed region snake method in segmentation of microorganisms in Single Exposure On- Line (SEOL) holographic microscopy images. 3D images of the microorganisms are digitally reconstructed and numerically focused from any arbitrary depth from a single recorded digital hologram without mechanical scanning. Living organisms are non-rigid and they vary in shape and size. Moreover, they often do not exhibit clear edges in digitally reconstructed SEOL holographic images. Thus, conventional segmentation techniques based on the edge map may fail to segment these images. However, SEOL holographic microscopy provides both magnitude and phase information of the sample specimen, which could be helpful in the segmentation process. In this paper, we present a statistical framework based on the joint probability distribution of magnitude and phase information of SEOL holographic microscopy images and maximum likelihood estimation of image probability density function parameters. An optimization criterion is computed by maximizing the likelihood function of the target support hypothesis. In addition, a simple stochastic algorithm has been adapted for carrying out the optimization, while several boosting techniques have been employed to enhance its performance. Finally, the proposed method is applied for segmentation of biological microorganisms in SEOL holographic images and the experimental results are presented.


Rapid decomposition and visualisation of protein-ligand binding free energies by residue and by water.
Recent advances in computational hardware, software and algorithms enable simulations of protein-ligand complexes to achieve timescales during which complete ligand binding and unbinding pathways can be observed. While observation of such events can promote understanding of binding and unbinding pathways, it does not alone provide information about the molecular drivers for protein-ligand association, nor guidance on how a ligand could be optimised to better bind to the protein. We have developed the waterswap (C. J. Woods et al., J. Chem. Phys., 2011, 134, 054114) absolute binding free energy method that calculates binding affinities by exchanging the ligand with an equivalent volume of water. A significant advantage of this method is that the binding free energy is calculated using a single reaction coordinate from a single simulation. This has enabled the development of new visualisations of binding affinities based on free energy decompositions to per-residue and per-water molecule components. These provide a clear picture of which protein-ligand interactions are strong, and which active site water molecules are stabilised or destabilised upon binding. Optimisation of the algorithms underlying the decomposition enables near-real-time visualisation, allowing these calculations to be used either to provide interactive feedback to a ligand designer, or to provide run-time analysis of protein-ligand molecular dynamics simulations.


Generation of focal pattern with controllable polarization and intensity for laser beam passing through a multi-mode fiber.
Similar to coherent light passing through a scattering medium, the propagation of coherent light through a multi-mode fiber (MMF) will result in a random speckle field. For a non-polarization maintaining MMF, the randomization can be observed not only in the intensity distribution, but also in the polarization state. In this paper, we propose a new technique known as phase combination to control the optical field for the light passing through the MMF. We show that, based on this new technique, the random speckle pattern can be modulated into an intensity distribution of two bright focal spots with mutually perpendicular polarization by only one polarizer. In particular, the intensity distribution of these two focal spots can be quantitatively controlled. This technique may find applications in medical imaging, nonlinear optics and optical communication etc.


A new syndrome of congenital hypoparathyroidism, severe growth failure, and dysmorphic features.
Twelve infants (six boys, six girls) with severe hypocalcaemic tetany or convulsions were seen over a three year period. Nine patients were symptomatic in the newborn period. Their hypocalcaemia was associated with hyperphosphataemia and very low concentrations of immunoreactive parathyroid hormone. None of the babies suffered from congenital cardiac disease. Cell mediated immunity, measured in five patients, was normal. There were no chromosomal abnormalities but all patients shared several dysmorphic features including deep set eyes, microcephaly, thin lips, beaked nose tip, external ear anomalies, micrognathia, and depressed nasal bridge. Mental retardation of varying degree was found in all patients. All had severe intrauterine and postnatal growth retardation. Four patients have died. The remaining eight patients are on treatments with vitamin D and calcium supplements with no change in their growth pattern. We believe that this association of congenital hypoparathyroidism with severe growth failure and dysmorphism represents a new syndrome.


Sub national variation and inequalities in under-five mortality in Kenya since 1965.
Despite significant declines in under five mortality (U5M) over the last 3 decades, Kenya did not achieve Millennium Development Goal 4 (MDG 4) by 2015. To better understand trends and inequalities in child mortality, analysis of U5M variation at subnational decision making units is required. Here the comprehensive compilation and analysis of birth history data was used to understand spatio-temporal variation, inequalities and progress towards achieving the reductions targets of U5M between 1965 and 2013 and projected to 2015 at decentralized health planning units (counties) in Kenya. Ten household surveys and three censuses with data on birth histories undertaken between 1989 and 2014 were assembled. The birth histories were allocated to the respective counties and demographic methods applied to estimate U5M per county by survey. To generate a single U5M estimate for year and county, a Bayesian spatio-temporal Gaussian process regression was fitted accounting for variation in sample size, surveys and demographic methods. Inequalities and the progress in meeting the goals set to reduce U5M were evaluated subnationally. Nationally, U5M reduced by 61·6%, from 141·7 (121·6-164·0) in 1965 to 54·5 (44·6-65·5) in 2013. The declining U5M was uneven ranging between 19 and 80% across the counties with some years when rates increased. By 2000, 25 counties had achieved the World Summit for Children goals. However, as of 2015, no county had achieved MDG 4. There was a striking decline in the levels of inequality between counties over time, however, disparities persist. By 2013 there persists a 3·8 times difference between predicted U5M rates when comparing counties with the highest U5M rates against those with the lowest U5M rates. Kenya has made huge progress in child survival since independence. However, U5M remains high and heterogeneous with substantial differences between counties. Better use of the current resources through focused allocation is required to achieve further reductions, reduce inequalities and increase the likelihood of achieving Sustainable Development Goal 3·2 on U5M by 2030.


The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis.
Gliomas are the most common primary tumours of the central nervous system, with nearly 15,000 diagnosed annually in the United States and a lethality approaching 80% within the first year of glioblastoma diagnosis. The marked induction of angiogenesis in glioblastomas suggests that it is a necessary part of malignant progression; however, the precise molecular mechanisms underlying the regulation of brain tumour growth and angiogenesis remain unresolved. Here we report that a candidate tumour suppressor gene, ING4, is involved in regulating brain tumour growth and angiogenesis. Expression of ING4 is significantly reduced in gliomas as compared with normal human brain tissue, and the extent of reduction correlates with the progression from lower to higher grades of tumours. In mice, xenografts of human glioblastoma U87MG, which has decreased expression of ING4, grow significantly faster and have higher vascular volume fractions than control tumours. We show that ING4 physically interacts with p65 (RelA) subunit of nuclear factor NF-kappaB, and that ING4 regulates brain tumour angiogenesis through transcriptional repression of NF-kappaB-responsive genes. These results indicate that ING4 has an important role in brain tumour pathogenesis.


The linear computational algorithm of cerebellar Purkinje cells.
The orchestration of simple motor tasks by the cerebellum results in coordinated movement and the maintenance of balance. The cerebellum integrates sensory and cortical information to generate the signals required for the coordinated execution of simple motor tasks. These signals originate in the firing rate of Purkinje cells, each of which integrates sensory and cortical information conveyed by granule cell synaptic inputs. Given the importance of the granule cell input-Purkinje cell output function for cerebellar computation, this algorithm was determined. Using several stimulation paradigms, including those that mimicked patterns of granule cell activity similar to those observed in vivo, we quantified the poststimulus maximum firing rate and number of extra spikes in response to granule cell synaptic input. Both of these parameters linearly encoded the strength of synaptic input when inhibitory synaptic transmission was blocked. This linear algorithm was independent of the location or temporal pattern of synaptic input. With inhibitory synaptic transmission intact, the maximum firing rate, but not the number of extra spikes, encoded the strength of granule cell synaptic input. Furthermore, the maximum firing rate of Purkinje cells linearly encoded the strength of synaptic input whether or not the activation of granule cells resulted in a pause in Purkinje cell firing. On the basis of the data presented, we propose that Purkinje cells encode the strength of granule cell synaptic input in their maximum firing rate with a linear algorithm.


Toxicity of non-steroidal anti-inflammatory drugs to Gyps vultures: a new threat from ketoprofen.
Three Gyps vulture species are on the brink of extinction in South Asia owing to the veterinary non-steroidal anti-inflammatory drug (NSAID) diclofenac. Carcasses of domesticated ungulates are the main food source for Asia's vultures and birds die from kidney failure after consuming diclofenac-contaminated tissues. Here, we report on the safety testing of the NSAID ketoprofen, which was not reported to cause mortality in clinical treatment of scavenging birds and is rapidly eliminated from livestock tissues. Safety testing was undertaken using captive non-releasable Cape griffon vultures (Gyps coprotheres) and wild-caught African white-backed vultures (G. africanus), both previously identified as susceptible to diclofenac and suitable surrogates. Ketoprofen doses ranged from 0.5 to 5 mg kg(-1) vulture body weight, based upon recommended veterinary guidelines and maximum levels of exposure for wild vultures (estimated as 1.54 mg kg(-1)). Doses were administered by oral gavage or through feeding tissues from cattle dosed with ketoprofen at 6 mg kg(-1) cattle body weight, before slaughter. Mortalities occurred at dose levels of 1.5 and 5 mg kg(-1) vulture body weight (within the range recommended for clinical treatment) with the same clinical signs as observed for diclofenac. Surveys of livestock carcasses in India indicate that toxic levels of residual ketoprofen are already present in vulture food supplies. Consequently, we strongly recommend that ketoprofen is not used for veterinary treatment of livestock in Asia and in other regions of the world where vultures access livestock carcasses. The only alternative to diclofenac that should be promoted as safe for vultures is the NSAID meloxicam.


Cloning and characterization of the maize An1 gene.
The Anther ear1 (An1) gene product is involved in the synthesis of ent-kaurene, the first tetracyclic intermediate in the gibberellin (GA) biosynthetic pathway. Mutations causing the loss of An1 function result in a GA-responsive phenotype that includes reduced plant height, delayed maturity, and development of perfect flowers on normally pistillate ears. The an1::Mu2-891339 allele was recovered from a Mutator (Mu) F2 family. Using Mu elements as molecular probes, an An1-containing restriction fragment was identified and cloned. The identity of the cloned gene as An1 was confirmed by using a reverse genetics screen for maize families that contain a Mu element inserted into the cloned gene and then by demonstrating that the insertion causes an an1 phenotype. The predicted amino acid sequence of the An1 cDNA shares homology with plant cyclases and contains a basic N-terminal sequence that may target the An1 gene product to the chloroplast. The sequence is consistent with the predicted subcellular localization of AN1 in the chloroplast and with its biochemical role in the cyclization of geranylgeranyl pyrophosphate, a 20-carbon isoprenoid, to ent-kaurene. The semidwarfed stature of an1 mutants is in contrast with the more severely dwarfed stature of GA-responsive mutants at other loci in maize and may be caused by redundancy in this step of the GA biosynthetic pathway. DNA gel blot analysis indicated that An1 is a single-copy gene that lies entirely within the deletion of the an1-bz2-6923 mutant. However, homozygous deletion mutants accumulated ent-kaurene to 20% of the wild-type level, suggesting that the function of An1 is supplemented by an additional activity.


Differential effect of physical exercise routines on ventricular myosin and peripheral catecholamine stores in normotensive and spontaneously hypertensive rats.
The influence of the adrenergic system on the population of ventricular myosin isoenzymes under physiological conditions was assessed by subjection of normotensive and spontaneously hypertensive rats (SHR) to different types of physical exercise that increased the activity of the peripheral adrenergic system to varying degrees. The routines, which were 5-6 weeks in duration, involved the mild exercise of enforced swimming (2 x 90 min/day), spontaneous running (daily, about 15 km/10-12 hr) that resulted in absolute ventricular hypertrophy, and enforced running of low intensity (daily, 2 x 1.8 km/3 hr) but associated with marked stressors. Swimming and spontaneous running reduced the high blood pressure of SHR, whereas enforced running increased it. In both strains, the myosin isoenzymes were redistributed in the direction of V1 after swimming but not after running. In SHR, therefore, reduction of pressure load seems insufficient for induction of a higher proportion of V1. The unique and, until now, unexplained effect of swimming was attributed to the pronounced activation of the peripheral adrenergic system as judged from catecholamine stores of ventricles and adrenal glands. Only swimming increased the norepinephrine content of ventricles and adrenal glands in normotensive rats. Swimming also had the strongest influence in SHR. Further evidence for the influence of the adrenergic system came from the effect of selective cardiac beta-blockade with atenolol (50 mg/kg/day). The diminished adrenergic drive of the heart reduced the proportion of V1 to a greater extent in the swimming rats than in the sedentary rats. Taken together, the data demonstrate that substantial changes in adrenergic activity occur under physiological conditions associated with an altered myosin heavy-chain expression.


Inter-relationships between inflammatory mediators released from colonic mucosa in ulcerative colitis and their effects on colonic secretion.
Metabolites of arachidonic acid have been implicated in the pathophysiology of ulcerative colitis-they can stimulate intestinal secretion, increase mucosal blood flow, and influence smooth muscle activity. The influence on the mucosal transport function of culture medium in which colonic mucosal biopsy specimens had been incubated was investigated using rat stripped distal colonic mucosa in vitro as the assay system. Colonic tissue from patients with colitis and from control subjects was cultured. Medium from inflamed tissue contained more prostaglandin E2 (PGE2) and leukotriene D4 (LTD4) and evoked a greater electrical (secretory) response in rat colonic mucosa than control tissue medium. In inflamed tissue, cyclo-oxygenase inhibition (indomethacin) attenuated PGE2 but increased LTD4 production; conversely lipoxygenase inhibition (ICI 207968) inhibited LTD4 production but enhanced PGE2 output. Each inhibitor alone enhanced the electrical response in the rat colon. Inhibition of both enzymes (indomethacin plus ICI 207968) caused a fall in both PGE2 (82%) and LTD4 (89%) production and in the electrical response (57%). Inflamed tissue treated with a phospholipase A2 inhibitor (mepacrine) produced less PGE2, LTD4, and electrical responses when compared with inflamed tissue, either untreated (91%, 92%, and 79% respectively) or treated with cyclo-oxygenase and lipoxygenase inhibition. Incubation with bradykinin stimulated eicosanoid release and electrical response, while a bradykinin antagonist caused a modest inhibition. Analysis of these observations suggests that a combination of arachidonic acid derivatives accounts for about half the secretory response. Other products of phospholipase A2 activity are probably responsible for much of the remainder, leaving up to 20% the result of types of mediator not determined in this study.


Activation of Ftz-F1-Responsive Genes through Ftz/Ftz-F1 Dependent Enhancers.
The orphan nuclear receptor Ftz-F1 is expressed in all somatic nuclei in Drosophila embryos, but mutations result in a pair-rule phenotype. This was explained by the interaction of Ftz-F1 with the homeodomain protein Ftz that is expressed in stripes in the primordia of segments missing in either ftz-f1 or ftz mutants. Ftz-F1 and Ftz were shown to physically interact and coordinately activate the expression of ftz itself and engrailed by synergistic binding to composite Ftz-F1/Ftz binding sites. However, attempts to identify additional target genes on the basis of Ftz-F1/ Ftz binding alone has met with only limited success. To discern rules for Ftz-F1 target site selection in vivo and to identify additional target genes, a microarray analysis was performed comparing wildtype and ftz-f1 mutant embryos. Ftz-F1-responsive genes most highly regulated included engrailed and nine additional genes expressed in patterns dependent on both ftz and ftz-f1. Candidate enhancers for these genes were identified by combining BDTNP Ftz ChIP-chip data with a computational search for Ftz-F1 binding sites. Of eight enhancer reporter genes tested in transgenic embryos, six generated expression patterns similar to the corresponding endogenous gene and expression was lost in ftz mutants. These studies identified a new set of Ftz-F1 targets, all of which are co-regulated by Ftz. Comparative analysis of enhancers containing Ftz/Ftz-F1 binding sites that were or were not bona fide targets in vivo suggested that GAF negatively regulates enhancers that contain Ftz/Ftz-F1 binding sites but are not actually utilized. These targets include other regulatory factors as well as genes involved directly in morphogenesis, providing insight into how pair-rule genes establish the body pattern.


Honest Signals of Status: Facial and Bodily Dominance Are Related to Success in Physical but Not Nonphysical Competition.
Recent studies suggest that both facial and bodily dominance promote high status positions and predict status-seeking behaviors such as aggression and social dominance. An evolutionarily relevant context in which associations between these dominance signals and status outcomes may be prevalent are face-to-face status contests. The present study examined whether facial and bodily dominance predicted success in dyadic competitions (one physical discipline, arm wrestling, and three nonphysical disciplines) in men (N = 125) in a controlled laboratory setting. Men's bodies and faces were independently rated for physical dominance, and associations of these ratings with contest outcomes as well as mediating and moderating variables (such as physical strength, body height, trait dominance, baseline and reactive testosterone) were examined. Both facial and bodily dominance positively predicted success in the physical discipline, mediated by physical strength, but not in the three nonphysical disciplines. Our findings demonstrate that facial and bodily physical dominance may be honest signals for men's formidability and hence status potential, at least in a physically competitive context.


The impact of bilateral therapy on upper limb function after chronic stroke: a systematic review.
To determine the evidence for bilateral therapy interventions aimed at improving upper limb (UL) function in adults with a range of UL activity limitations due to a first time chronic stroke. Seven databases were searched prior to 2008 for articles reporting experimental studies investigating bilateral UL interventions on functional outcome in participants with a first stroke, 6 or more months prior. Included articles were evaluated with the quality index, a tool which evaluates the quality of both randomised and non-randomised studies. Data relating to study design and functional outcome were extracted. Nine articles were included; three reported on randomised controlled trials (RCT) and six on cohort studies. Eight studies incorporated a mechanical device as their bilateral intervention. Bilateral arm training with rhythmic auditory cueing (BATRAC) was the most commonly used mechanically based intervention, and three of the four uncontrolled BATRAC studies reported significant improvements in UL function post-intervention, however these results were not substantiated by a RCT study of the BATRAC intervention. One study demonstrated significant functional improvements after 6 days of training with a non-mechanical bilateral task. Of the four studies that performed a follow-up assessment, three reported significant improvement in UL function. Quality index ratings of the included studies ranged from 18 to 25 out of 27. There is some evidence that bilateral therapy improves function in adults with chronic stroke, however more quality RCTs are required to strengthen this evidence.


BAX and BCL-2 polymorphisms, as predictors of proliferative vitreoretinopathy development in patients suffering retinal detachment: the Retina 4 project.
To compare the distribution of BCL-2 -938C>A (rs2279115) and BAX -248G>A (rs4645878) genotypes among European subjects undergoing rhegmatogenous retinal detachment (RRD) surgery in relation to the further development of proliferative vitreoretinopathy (PVR). A case-control gene association study, as a part of Retina 4 project, was designed. rs2279115 and rs4645878 polymorphisms were analysed in 555 samples from patients with RRD (134 with PVR secondary to surgery). Proportions of genotypes and AA homozygous groups of BCL-2 and BAX polymorphisms between subsamples were analysed in two phases. Genotypic and allelic frequencies were compared in global sample and in subsamples. BAX: Differences were observed in the genotype frequencies and in AA carriers between controls and cases in the global series. The odds ratio (OR) of A carriers in the global sample was 1.7 (95% CI: 1.23-2.51). Proportions of genotypes in Spain + Portugal were significant different. The OR of A carriers from Spain and Portugal was 1.8 (95% CI: 1.11-2.95). BCL-2: No significant differences were observed in genotype frequencies. However, proportions of genotypes in Spain + Portugal were significant. A protective effect (OR: 0.6 95% CI: 0.43-0.96) was found in A carriers from Spain and Portugal. Results suggest that A allele of rs4645878 could be a biomarker of high risk of developing PVR in patients undergoing RD surgery. The possible role of BCL-2 (inhibitor of necroptosis pathway) as a possible new target in PVR prophylaxis should be investigated.